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Here, we show that the meroterpenoid cyclosmenospongine from\n                    <jats:italic>Spongia sp<\/jats:italic>\n                    . reshapes immune cell lipidomes, shifting them from pro\u2010inflammatory toward anti\u2010inflammatory and pro\u2010resolving mediators. Structural variation yielded derivatives that context\u2010dependently inhibit leukotriene biosynthesis to varying extents while upregulating pro\u2010resolving lipid mediators, epoxyeicosatrienoic acids, endocannabinoids, sphingosine\u20101\u2010phosphate, and others in resting and activated innate immune cells in vitro, as well as in self\u2010resolving murine peritonitis and fibrosis in vivo. Mechanistically, meroterpenoids target 5\u2010lipoxygenase or 5\u2010lipoxygenase\u2010activating protein, promote 15\u2010lipoxygenase\u20101 translocation to particulate sites, and inhibit monoacylglycerol lipase. They also redirect arachidonic acid from neutral lipids to specific phospholipids while increasing free arachidonic acid levels. Furthermore, meroterpenoids reprogram immune cell lipid metabolism by reducing neutral lipid, triacylglycerol, and cholesteryl ester levels, a shift that correlates with a lower capacity for leukotriene biosynthesis and is phenocopied by inhibiting sterol\u2010O\u2010acyltransferase, which catalyzes cholesterol esterification for storage, and diacylglycerol acyltransferase\u20101\/2, which catalyze the final step in triacylglycerol biosynthesis. In conclusion, specific meroterpenoids exert anti\u2010inflammatory effects by rewiring lipid mediator biosynthesis through structure\u2010controlled switches in lipid mediator classes, and an unexpected link between lipogenesis and inflammation.\n                  <\/jats:p>","DOI":"10.1002\/advs.76861","type":"journal-article","created":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T11:52:00Z","timestamp":1787053920000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Reorganization of Innate Immune Cell Lipid Profiles by Bioinspired Meroterpenoids to Limit Inflammation"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0385-7216","authenticated-orcid":false,"given":"Lorenz","family":"Waltl","sequence":"first","affiliation":[{"name":"Michael Popp Institute and Center for Molecular Biosciences (CMBI) University of Innsbruck  Innsbruck Austria"},{"name":"Institute of Human Genetics Medical University of Innsbruck  Innsbruck Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-0220-5876","authenticated-orcid":false,"given":"David","family":"Holubek","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Sciences and Excellence Field BioHealth, NAWI Graz University of Graz.  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